Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histamine is known to have a profound effect on capillary permeability in nonrenal tissues and this effect is presumably mediated by cyclic (c)AMP. Because in our previous experiments we found that histamine stimulates cAMP accumulation in glomeruli (Torres, V. E., T. E. Northryn, R. M. Edwards, S. V. Shah, and T. P. Dousa. 1978. Modulation of cyclic nucleotides in isolated rat glomeruli. J. Clin. Invest.62: 1334.), we now explored whether this amine is formed in renal tissue, namely in glomeruli, and whether its renal metabolism is altered in experimental nephrosis induced by puromycin aminonucleoside (PA) in rats. In normal rats, histamine content was higher (Delta + 240%) in cortex than in medulla. In glomeruli isolated from renal cortex, histamine content was significantly higher (Delta + 260%) than in tubules. Incubation of isolated glomeruli with l-histidine resulted in a time-dependent increase of histamine content in glomeruli, but no change was found in tubules. The increase in glomerular histamine was blocked by the histidine decarboxylase inhibitor bromocresine. In rats with PA nephrosis induced by a single intraperitoneal injection of PA (15 mg/100 g body wt) urinary excretion of histamine was markedly increased (>Delta + 200%), but control rats did not differ from rats with PA nephrosis in urinary excretions of l-histidine and of creatinine. At the peak of proteinuria (day 9 after injection of PA) the plasma level of histamine was slightly elevated, and plasma histidine slightly decreased in animals that developed PA nephrosis. The content of histamine was markedly higher and the level of histidine was significantly lower in the renal cortex of PA-nephrotic rats as compared with controls; PA-nephrotic and control rats did not differ in the content of histidine and histamine in the liver. In addition, the content of histamine was higher in glomeruli isolated from PA-nephrotic rats; lesser difference was found in cortical tubules. The results further indicate that PA-nephrotic rats have higher content of histamine in the renal cortex, predominently in glomeruli with increased urinary histamine excretion. The elevated renal cortical histamine is not due to higher availability of histamine precursor l-histidine. Results thus show that glomeruli are a major site of intrarenal histamine synthesis and accumulation, and also suggest that abnormal renal metabolism of this amine in PA nephrosis may be related, as a cause or as a consequence, to the pathogenesis of this disease.
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PMID:Dynamics of renal histamine in normal rat kidney and in nephrosis induced by aminonucleoside of puromycin. 705 51

Dietary phosphorus restriction (PR) prevents uremia in rats with nephrotoxic serum nephritis (NSN). One possible mechanism by which PR could be protective would be through the suppression of parathyroid hormone. To evaluate this possibility two separate protocols were designed. In the first rats were thyroparathyroidectomized (TPTX) before (n = 11) or 5 wk after (n = 7) NSN induction and compared to sham-operated parathyroid intact rats with NSN (n = 12). At the end of the 23-wk study, intact rats were azotemic, plasma creatinine 3.80+/-0.81 mg/100 ml vs. 0.65+/-0.07 for TPTX rats (P < 0.001). During the study 75% of intact rats died of uremia in contrast to none of the TPTX rats (P < 0.001). Renal histological damage was greatly diminished and calcification prevented in TPTX rats. The proteinuria of the heterologous phase was unaffected, but the protein excretion and hypertriglyceridemia (HTG) of the autologous phase were markedly decreased in the TPTX rats. The degree of HTG and proteinuria had a high positive correlation (P < 0.001). Late TPTX also produced significant decreases in proteinuria and HTG regardless of the degree of azotemia, and prevented azotemia if the plasma creatinine at the time of TPTX was </=0.85 mg/100 ml. In additional studies selective parathyroidectomy (PTX) was performed. The adequacy of this procedure was documented by showing a similar fall in plasma Ca and urinary cyclic AMP in PTX animals as found in TPTX animals. However, selective PTX had no effect on proteinuria, histologic damage, or functional deterioration. These studies further showed that early, histologic damage and functional deterioration preceeded renal parenchymal calcification. Because animals were pair fed and both groups were given 1,25-dihydroxycholecalciferol to normalize serum Ca and P levels these studies exclude alterations in plasma Ca and P levels, dietary intake, urinary P excretion, and vitamin D administration in promoting the protective effect of TPTX on renal function. We conclude that TPTX is equally effective in preventing functional deterioration and more effective in reducing proteinuria in NSN than PR. The mechanism of this protective effect remains to be elucidated, since it does not primarily involve either the elimination of parathyroid hormone or the prevention of renal parenchymal calcification.
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PMID:Effect of thyroparathyroidectomy and parathyroidectomy on renal function and the nephrotic syndrome in rat nephrotoxic serum nephritis. 727 65

A 4-3/12 old boy with a hypophosphoremic coma (serum phosphorus: 0.4 mg./dl.) is presented. The favoring conditions appear to be related to acute renal failure in polyuric phase with high phosphorus excretion, low phosphorus intake, rapid transit from a catabolic to an anabolic state with previous malnutrition and parenteral feeding, oral aluminum hydroxide gel administration and lung infectious disease. The clinical, biochemical data, evolution and physiologic mechanisms are commented, specially those of erythrocyte, leucocyte and platelet disfunction related to ATP, AMP and 2.3 DPG deficiency. Proteinuria and hematuria during phosphorus depletion are emphasized. The alarm symptoms and treatment are indicated.
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PMID:[Hypophosphatemic coma (author's transl)]. 733 2

APRT deficiency is an enzyme disorder which is inherited as an autosomal recessive trait. The use of adenine in purine metabolism is disturbed and it accumulates in the body, where it is oxidised by xanthine oxidase to poorly insoluble 2, 8-dihydroxyadenine (DHA). The dihydroxyadenine forms stones which cause recurrent urolithiasis, frequent episodes of urinary tract infection or interstitial nephritis, and finally renal insufficiency in some cases. We report a case of APRT deficiency discovered by urine examination. The patient was a 33-year-old man who had never had any episodes of urolithiasis. He was admitted to our hospital because of pseudoarthrosis of his left arm caused by a traffic accident. His urinalysis revealed no proteinuria nor hematuria, but disclosed numerous round brown crystals in the sediment. These crystals had the characteristics of 2, 8-DHA. The enzyme activity of APRT in his blood was completely deficient. He was diagnosed as an APRT* QO homozygote. In addition, diagnostic imaging revealed that his right kidney was poorly hypoplastic and the pelvis of his left kidney was extra-renal. The renal function was slightly disturbed. In Japan 6 cases of 2, 8-DHA urolithiasis associated with hypoplastic kidney had been reported by 1989. Theoretically, the incidence of hypoplastic kidney is around 20% of all 2, 8-DHA urolithiasis cases. We suspect a genetic correlation between hypoplastic kidney and APRT deficiency. This patient was treated with Allopurinol, which inhibits the process of xanthine oxidation, after which crystals were no longer detected in his urine.
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PMID:[A case of adenine phosphoribosyltransferase (APRT) deficiency discovered by urine examination]. 781 52

1. Excessive production of extracellular matrix is thought to be involved in the progression of glomerulonephritis and glomerulosclerosis. In chronic glomerulonephritis, fibronectin has been shown to accumulate in the glomeruli, accompanied by cell proliferation. 2. Glomerulonephritis was induced in rats by the injection of anti-glomerular basement membrane antibody. The rats showed proteinuria and histological alterations in the glomeruli. An increase in fibronectin levels in the culture medium of isolated nephritic glomeruli was confirmed, and was associated with the development of nephritis. Immunohistochemical staining demonstrated a marked accumulation of fibronectin in the glomeruli of nephritic rats. 3. Attenuated generation of cyclic AMP was also observed in the nephritic glomeruli treated with forskolin, prostaglandin E1 or adenosine. 4. Forskolin, prostaglandin E2 and 8-bromo-cyclic AMP markedly reduced the production of fibronectin by the nephritic glomeruli compared with controls in a dose-dependent manner. 8-Bromo-cyclic AMP suppressed the production of fibronectin by cultured mesangial cells. 5. These findings suggest that the attenuated generation of cyclic AMP in response to ligands is connected to the augmented accumulation of fibronectin in nephritic glomeruli, and may facilitate the development of methods for treating glomerulonephritis and glomerulosclerosis.
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PMID:Adenosine 3', 5' cyclic monophosphate attenuates the production of fibronectin in the glomeruli of anti-glomerular basement membrane antibody-associated nephritic rats. 1459 4

Mutations in ClC-5 (chloride channel 5), a member of the ClC family of chloride ion channels and antiporters, have been linked to Dent's disease, a renal disease associated with proteinuria. Several of the disease-causing mutations are premature stop mutations which lead to truncation of the C-terminus, pointing to the functional significance of this region. The C-terminus of ClC-5, like that of other eukaryotic ClC proteins, is cytoplasmic and contains a pair of CBS (cystathionine beta-synthase) domains connected by an intervening sequence. The presence of CBS domains implies a regulatory role for nucleotide interaction based on studies of other unrelated proteins bearing these domains [Ignoul and Eggermont (2005) Am. J. Physiol. Cell Physiol. 289, C1369-C1378; Scott, Hawley, Green, Anis, Stewart, Scullion, Norman and Hardie (2004) J. Clin. Invest. 113, 274-284]. However, to date, there has been no direct biochemical or biophysical evidence to support nucleotide interaction with ClC-5. In the present study, we have expressed and purified milligram quantities of the isolated C-terminus of ClC-5 (CIC-5 Ct). CD studies show that the protein is compact, with predominantly alpha-helical structure. We determined, using radiolabelled ATP, that this nucleotide binds the folded protein with low affinity, in the millimolar range, and that this interaction can be competed with 1 muM AMP. CD studies show that binding of these nucleotides causes no significant change in secondary structure, consistent with a model wherein these nucleotides bind to a preformed site. However, both nucleotides induce an increase in thermal stability of ClC-5 Ct, supporting the suggestion that both nucleotides interact with and modify the biophysical properties of this protein.
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PMID:Nucleotides bind to the C-terminus of ClC-5. 1668 97

Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute models of vascular injury. We hypothesized that aberrant nucleotide signaling would promote chronic glomerular injury in diabetic nephropathy. Inducing diabetes in ENTPD1-null mice with streptozotocin resulted in increased proteinuria and more severe glomerular sclerosis compared with matched diabetic wild-type mice. Diabetic ENTPD1-null mice also had more glomerular fibrin deposition and glomerular plasminogen activator inhibitor-1 (PAI-1) staining than wild-type controls. In addition, ENTPD1-null mice showed increased glomerular inflammation, in association with higher levels of monocyte chemoattractant protein-1 (MCP-1) expression. Mesangial cell PAI-1 and MCP-1 mRNA expression were upregulated by ATP and UTP but not ADP or adenosine in vitro. The stable nucleotide analog ATPgammaS stimulated sustained expression of PAI-1 and MCP-1 in vitro, whereas the stable adenosine analog NECA [5'-(N-ethylcarboxamido)adenosine] downregulated expression of both genes. Extracellular nucleotide-stimulated upregulation of MCP-1 is, at least in part, protein kinase C dependent. We conclude that ENTPD1 is a vascular protective factor in diabetic nephropathy that modulates glomerular inflammation and thromboregulation.
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PMID:The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy. 1747 21

Cyclooxygenase-2 (COX-2)-dependent prostaglandin E(2) (PGE(2)) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure (P(gc)) glomerular disease models. We previously showed that an in vitro surrogate for P(gc) (cyclical mechanical stretch) upregulates the expression of both COX-2 and the PGE(2) responsive E-Prostanoid receptor, EP(4) in cultured mouse podocytes. In the present study we further delineate the signaling pathways regulating podocyte COX-2 induction. Time course experiments carried out in conditionally-immortalized mouse podocytes revealed that PGE(2) transiently increased phosphorylated p38 MAPK levels at 10 min, and induced COX-2 protein expression at 4 h. siRNA-mediated knockdown of EP(4) receptor expression, unlike treatment with the EP(1) receptor antagonist SC 19220, completely abrogated PGE(2)-induced p38 phosphorylation and COX-2 upregulation suggesting the involvement of the EP(4) receptor subtype. PGE(2)-induced COX-2 induction was abrogated by inhibition of either p38 MAPK or AMP activated protein kinase (AMPK), and was mimicked by AICAR, a selective AMPK activator, and by the cAMP-elevating agents, forskolin (FSK) and IBMX. Surprisingly, neither PGE(2) nor FSK/IBMX-dependent p38 activation and COX-2 expression were blocked by PKA inhibitors or mimicked by 8-cPT-cAMP a selective EPAC activator, but were instead abrogated by Compound C, suggesting the involvement of AMPK. These results indicate that in addition to mechanical stretch, PGE(2) initiates a positive feedback loop in podocytes that drives p38 MAPK activity and COX-2 expression through a cAMP/AMPK-dependent, but PKA-independent signaling cascade. This PGE(2)-induced signaling network activated by increased P(gc) could be detrimental to podocyte health and glomerular filtration barrier integrity.
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PMID:PGE(2) induces COX-2 expression in podocytes via the EP(4) receptor through a PKA-independent mechanism. 1876 48

Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
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PMID:Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. 2001 31

In non-neuronal cells, glutamate is an extracellular signaling mediator. Since podocytes have glutamate-containing vesicles, we sought to determine glutamate receptor presence and action in glomerular cells. The metabotropic glutamate receptors (mGluR) 1, 5, 6, and 8 were found to be expressed in mouse brain and glomeruli; predominantly in podocytes. In two models of proteinuria (BalB/C mice with puromycin aminonucleoside- and doxorubicin-induced podocyte injury) we found that the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) attenuated albuminuria and improved the expression of the podocyte marker WT-1. TUNEL staining showed that the number of podocytes undergoing apoptosis was inversely correlated with the number of WT-1-positive cells in glomeruli. When podocytes were treated with DHPG in vitro, they generated cyclic AMP and activated CREB (cyclic AMP response element binding protein). The selective mGluR1/5 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid, the adenylate cyclase inhibitor SQ22536, and RNA interference knockdown of mGluR1 or mGluR5 all prevented DHPG-induced cAMP generation and CREB activation. DHPG inhibited apoptosis and the decrease of aminonucleoside-induced mitochondrial membrane potential in podocytes but had no effect in the presence of SQ22536 with knockdown mGluR1 or mGluR5. Thus, functional mGluR1 and mGluR5 are expressed in podocytes and their activation protects against albuminuria and podocyte apoptosis, processes that are, at least in part, dependent on cAMP.
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PMID:Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes. 2216 49


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